The primary goal has been the elucidation of the structure of reactive metabolites which are responsible for the carcinogenic, cytotoxic, and mutagenic activity of benzo[a]pyrene and other polycyclic hydrocarbons. The approach taken consists of: i) synthesis of primary oxidative metabolites as well as selected secondary oxidative metabolites, ii) study of the metabolism of these hydrocarbons with liver microsomes, as well as with purified and reconstituted hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for inherent mutagenicity of the synthetic metabolites toward bacterial and mammalian cells, iv) elucidation of the roles of the cytochrome P-450 system and epoxide hydrolase in potentiating or obliterating the mutagenicity of these metabolites, v) determination of the carcinogenic activity of these compounds, vi) determination of the rate of formation and nature of the products formed when reactive metabolites such as arene oxides and diol epoxides react with biopolymers and less complex model compounds. A general theory of hydrocarbon-induced carcinogenesis, the bay-region theory, has been formulated and its predictions are being tested with synthetic potential metabolites of several hydrocarbons. Based on the presently available data, the bay region theory has excellent predictive value. Current synthetic studies have provided enantiomerically pure bay-region diol epoxides of benzo[c]phenanthrene for use in biological studies. Kinetic studies have shown that DNA is an effective catalyst in the hydrolysis of bay-region diol epoxides, but only at low ionic strength. Potential agents for blocking tumorigenesis including riboflavin 5 feet-phosphate (FMN), ellagic acid and a variety of plant-derived phenols have been identified and their mechanism of action studied. A steric model for the catalytic binding site of cytochrome P-450c has been developed, and a new microsomal expoxide hydrolase has been discovered.